Progesterone Resistance in PCOS/PMOS: Molecular Insights and Therapeutic Perspectives

Background: Polycystic ovary syndrome (PCOS), recently renamed as Polycystic Ovary Morphology and Metabolic Syndrome (PMOS), is a leading cause of female infertility. Despite successful ovulation induction treatment, many patients still fail to achieve pregnancy. This discrepancy points to impaired endometrial receptivity, to which progesterone resistance is a contributing factor within a multifactorial pathogenesis. This review explores the molecular, clinical, and therapeutic aspects of progesterone resistance in PCOS/PMOS to improve patient management. Methods: A comprehensive literature search of PubMed, Scopus, and Web of Science was conducted, identifying 68 relevant studies for this review. Results: The negative effects of progesterone resistance are caused by several interacting factors. Chronic hyperinsulinemia traps the essential progesterone receptor co-activator FOXO1 in the cytoplasm. Additionally, high androgen levels lead to an overexpression of androgen receptors, which compete for shared cellular resources. Furthermore, chronic inflammation and M1 macrophage polarization disrupt the local immune balance, causing decidual cell senescence. These defects are also maintained by epigenetic changes. Conclusions: Overall, administering higher doses of progesterone is not sufficient to overcome these underlying barriers. Therefore, this review underlines the need for metabolically targeted treatments, such as lifestyle modifications, metformin, and inositols, which may improve the metabolic and endocrine environment associated with impaired endometrial responsiveness, although direct reversal of progesterone resistance requires further clinical validation.